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A Wetterholm, JZ Haeggstrom, B Samuelsson, W Yuan, B Munoz and CH Wong
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Leukotriene (LT) A4 hydrolase (EC 3.3.2.6) is a bifunctional zinc metalloenzyme that catalyzes the hydrolysis of the unstable epoxide intermediate LTA4 into the proinflammatory substance LTB4 and also exhibits an amidase/peptidase activity toward synthetic substrates. Based on proposed reaction mechanisms for other zinc hydrolases, we have synthesized inhibitors of LTA4 hydrolase and evaluated their effects on the formation of LTB4 from LTA4 using both purified enzyme and intact polymorphonuclear leukocytes. The two most effective inhibitors, an alpha-keto-beta-amino ester (compound IV) and a thioamine (compound VIII), exhibited IC50 values of 1.9 +/- 0.9 and 0.19 +/- 0.12 microM (mean +/- SD, n = 4), respectively. Compounds IV and VIII were also potent inhibitors of LTB4 biosynthesis in ionophore stimulated polymorphonuclear leukocytes with IC50 < 200 nM. At higher concentrations, the biosynthesis of 5-hydroxy-eicosatetraenoic acid was also inhibited with IC50 approximately 10 microM for both substances. In contrast, leukocyte 15-lipoxygenase and platelet LTC4 synthase activity were not inhibited by these substances at the highest concentrations tested, 50 and 10 microM, respectively. Compounds IV and VIII thus exhibit selectivity among enzyme activities in the arachidonic acid cascade. In conclusion, we describe two compounds that are among the most potent and selective inhibitors of LTA4 hydrolase and LTB4 biosynthesis by intact polymorphonuclear leukocytes, described thus far.
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